Method of cancer treatment

ABSTRACT

Methods of treating and inhibiting cancer in animals by administering a therapeutically effective amount of a pharmaceutical composition having benzimidazole of the general formula:  
                 
 
     wherein X is hydrogen, halogen, alkyl of less than 7 carbon atoms or alkoxy of less than 7 carbon atoms; n is a positive integer of less than 4; Y is hydrogen, chlorine, oxychloro, nitro, methyl or ethyl; and R is hydrogen, or an alkyl group of from 1 to 8 carbon atoms and R 2  is NHCOOR 1  wherein R 1  is aliphatic hydrocarbon of less than 7 carbon atoms, and preferably an alkyl group of less than 7 carbon atoms and pharmaceutically acceptable derivatives alone, or in combination, or in conduction with other therapeutic agents such as other cancer inhibiting compounds, and operative combinations thereof.

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] The present application is a continuation of U.S. Ser. No.09/374,717, filed Aug. 13, 1999.

TECHNICAL FIELD

[0002] The present invention relates to methods of using one or morebenzimidazole compounds and its pharmaceutically acceptable derivativesto treat and prevent cancer in both human and warm blooded animals. Inparticular, this invention relates to benzimidazole and its derivativesin cancer prevention and maintenance therapy.

BACKGROUND OF THE INVENTION

[0003] Cancers are a leading cause of death in animals and humans. Theexact cause of cancer is not known. There is evidence that certainactivities such as smoking or exposure to carcinogens may enhance therisk for certain types of cancers and tumors.

[0004] Treatment of cancer in the early stages typically comprise localtreatment such as, surgery and/or radiotherapy. While radiation therapyhas been widely used in managing cancerous diseases, it is limited bylack or radiosensitivity of specific regions of malignant tumors. Moreadvanced disease is treated by combining local treatment withchemotherapy. Although current chemotherapeutic agents have been shownto be effective against cancers and tumor cells, the use of combinedtreatment with all three regimens, surgery, radiotherapy, andchemotherapy, have not been shown to be effective against all cancer andtumor cells.

[0005] Much of the effort in therapeutics of cancer has focused oncancers that are metastasized. To date hormones, in particular estrogen,progesterone and testosterone, and some antibiotics produced by avariety of microbes, alkylating agents, and anti-metabolites form thebulk of therapies available to oncologists. Prostate cancer treatments,for example, rely on hormonal manipulation. However, in despite theinitial high response rate, patients often develop hormone-refractorytumors. Unfortunately, the clinical usefulness of these treatments havebeen limited. This is because these therapies demonstrate only marginallevels of activity or generally unacceptable levels of cytotoxicity orboth, thereby dinunis lung their usefulness in cancer treatment. Overallthe results of cytotoxic chemotherapy have been disappointing indicatinga long felt need for a new approach or treatment. Ideally cytotoxicagents that have specificity for cancer and tumor cells while notaffecting normal cells would be extremely desirable. Unfortunately, nonehave been found and instead agents which target especially rapidlydividing cells (both tumor and normal) have been used.

SUMMARY OF THE INVENTION

[0006] A method of preventing cancer in a patient, especially coloncancer is disclosed. The patients are treated utilizing a benzimidazolecompounds. its pharmaceutical addition salts, pharmaceuticallyacceptable derivatives or its prodrugs selected from the group havingthe formula:

[0007] wherein X is hydrogen, halogen, alkyl of less than 7 carbon atomsor alkoxy of less than 7 carbon atoms; n is a positive integer of lessthan 4; Y is hydrogen, chloro, oxychloro, nitro, methyl or ethyl; and Ris hydrogen, or an alkyl group of from 1 to 8 carbon atoms and R₂ isNHCOOR₁ wherein R₁ is aliphatic hydrocarbon of less than 7 carbon atoms,and preferably an alkyl group of less than 7 carbon atoms is claimed.

[0008] Preferably the subjects are treated with compounds having theformula:

[0009] wherein R is an alkyl of 1 through 8 carbon atoms and R₂ isselected from the group consisting of NHCOOR₁, wherein R₁ is methyl,ethyl or isopropyl and the non-toxic, pharmaceutically acceptable acidaddition salts with both organic and inorganic acids. The most preferredcompound is 2-methoxycarbonylamino-benzimidazole and itspharmaceutically acceptable salts.

[0010] Specifically, the invention provides a method of preventingvarious cancers associated with neoplasm or malignant tumors, forexample, leukemia, sarcomas and lymphomas including prostate cancer,breast cancer, lung cancer, melanoma, and the like.

[0011] The present invention provides a method of treatment in a subjectcomprising adiministering a therapeutic amount of benzimidazole or apharmaceutically acceptable derivative to humans or animals.

DETAILED DESCRIPTION OF THE INVENTION A. DEFINITIONS

[0012] As used herein, a “pharmaceutically acceptable” component is onethat is suitable for use with humans and/or animals without undueadverse side effects (such as toxicity, irritation, and allergicresponse) commensurate with a reasonable benefit/risk ratio.

[0013] As used herein, the term “therapeutically effective amount” ismeant an amount of a compound of the present invention effective toyield a desired therapeutic response. For example to prevent cancer ortreat the symptoms of cancer in a host or an amount effective to treatcancer. The specific “therapeutically effective amount” will, obviously,vary with such factors as the particular condition being treated, thephysical condition of the patient, the type of mammal being treated, theduration of the treatment, the nature of concurrent therapy (if any),and the specific formulations employed and the structure of thecompounds or its derivatives.

[0014] As used herein, a “pharmaceutical addition salts” is salt of thebenzimidazole compound with an organic or inorganic acid. Thesepreferred acid addition salts are chlorides, bromides, sulfates,nitrates, phosphates, sulfonates, formates, tartrates, maleates,malates, citrates, benzoates, salicylates, ascorbates, and the like.

[0015] As used herein, a “pharmaceutical carrier” is a pharmaceuticallyacceptable solvent, suspending agent or vehicle for delivering theanti-cancer agent to the animal or human. The carrier may be liquid orsolid and is selected with the planned manner of administration in mind.

[0016] As used herein, “cancer” refers to all types of cancers orneoplasm or malignant tumors found in mammals. Cancer includes sarcomas,lymphomas and other cancers. The following types are examples, but are,but is not intended to be limited to these particular types of cancers:prostate, colon, breast, both the MX-1 and the MCF lines, pancreatic,neuroblastoma, rhabdomysarcoma, home, lung, murine, melanoma, leukemia,pancreatic, melanoma, ovarian, brain, head & neck, kidney, mesothelioma,sarcoma, Kaposi's, sarcoma, stomach, and uterine.

[0017] As used herein, the term “cell” include but is not limited tomammalian cells (e.g., mouse cells rat cells or human cells).

[0018] As used herein, the “anti-cancer compounds” are thebenzimidazoles, their salts, and prodrugs thereof. The exactbenzimidazoles are described in detail below. The preferred materialsare the products sold under the names “benomyl®” or “carbendazim®” byBASF and Hoechst, DuPont and MSD-AgVet.

[0019] As used herein, the term “inventive group” refers to thebenzimidazoles, and their salts or prodrugs.

[0020] As used herein, “a subject in need thereof” is a patient, animal,mammal or human, who will benefit from the method of this invention.This patient may be a person genetically disposed to cancer or a patientwho is believed to be at risk for developing cancer.

[0021] As used herein, the term “prodrugs” are considered to be anycovalently bonded carriers which release the active parent drugaccording to the formula of derivatives described above in vivo, invitro or ex vivo.. Prodrugs of the benzimidozole or urea derivatives areprepared by modifying functional groups present in the compounds in sucha way that the modifications are cleaved, either in routine manipulationor in vivo, in vitro, or ex vivo to the parent compounds. Prodrugsinclude compounds wherein free hydroxyl, sulfhydryl, or amine groups arebonded to any group that, when administered to a mammalian subject,cleaves to form a free hydroxyl, amino, or sulfhydryl group,respectively. Examples of prodrugs include, but are not limited to,acetate, formate, or benzoate derivatives of alcohol and aminefunctional groups in the arylthiazolyl thiourea derivatives orarylthiazoloyl urea derivative; phosphate esters, dimethylglycineesters, aminoalkylbenzyl esters, aminoalkyl esters and carboxyalkylesters of alcohol and phenol functional groups in the arylthiazolylthiourea derivatives or arylthiazoloyl urea derivative; and the like.

B. METHOD OF THE PRESENT INVENTION

[0022] The present invention provides a method for reducing orinhibiting infected cells or population of cells by administering aneffective amount of a benzimidazole compound and/or pharmaceuticallyacceptable derivatives, such that (1) cancer is prevented and (2)metastasis and spreading of cancerous is inhibited, and (3) the life ofthe patient is prolonged.

[0023] The compounds used in the method of the present invention areknown for their antifungal activities. They are systemic fungicides usedto prevent and eradicate fungi. In the method of the present inventionthe compounds have been found to have anticancer activity. The compoundsused alone and/or when combined with carriers, provide compositions fortreating and preventing the spreading of cancer in vitro, ex vivo or invivo. The compounds can be combined with various pharmaceuticallyacceptable carriers as defined below.

C. METHOD OF ADMINISTERING THE ANTI-CANCER COMPOUND AND DOSAGE DELIVERYFORMS

[0024] The compounds of the present invention can be administered by anysuitable means including, but not limited to, for example, oral, rectal,nasal, topical (including transdermal, aerosol, buccal and sublingual),vaginal, parenteral (including subcutaneous, intramuscular, intravenousand intradermal), intravesical or injection into or around the tumor.

[0025] The dosage amounts are based on the effective inhibitoryconcentrations observed in antitumorigencity studies. The preferredroute will vary with the (1) condition and age of the recipient, (2)tumor being treated (3) nature of tumor and (4) desired blood levels. Itis believed that parenteral treatment by intravenous, subcutaneous, orintramuscular application of the compounds of the present inventionformulated with an appropriate carrier, other anticancer agents orcompounds or diluents to facilitate application will be the preferredmethod of administering the compounds to warm blooded animals.

[0026] The benzimidazole compounds, pharmaceutically acceptablyderivatives, in particular 2-methoxycarbonylamino-benzimidazole and itspharmaceutically acceptable salts or prodrugs are preferably micronizedor powdered so that it is more easily dispersed and solubilized by thebody. Processes for grinding or pulverizing drugs are well known in theart. For example, a hammer mill or similar milling device can be used.The preferred particle size is less than about 100μ and preferably lessthan 50μ. These compounds are not very soluble, and therefore arepreferably given in tablet form or as a suspension. Suitable methods ofadministering the compounds of the present invention and dosage formscan be found herein below.

[0027] The benzimidazole compounds or pharmaceutically acceptablederivatives of this invention can be administered as treatment forcancer by any means that produces contact of the active agent with theagent's site of action in the body. They can be administered by anyconventional means available for use in conjunction withpharmaceuticals, either as individual therapeutic agents or in acombination of therapeutic agents. Preferably the compounds of thepresent invention are administered as a pharmaceutical formulationcomprising at least one compound of the present invention, as definedabove, together with one or more pharmaceutically acceptable carriers.It can be co-administered in the form of a tablet or capsule, as anagglomerated powder or in a liquid form or as a lipsome.

[0028] The compounds of the present invention may also be adnunisteredin the form of liposome delivery systems, such as small unilamellarvesicles, large unilamallar vesicles, and multilamellar vesicles.Liposomes can be formed from a variety of phospholipids, such ascholesterol, stearylamine, or phosphatidylcholines.

[0029] The benzimidazole compounds or therapeutically acceptablederivatives of the present invention can also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxylpropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention can be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, andcrosslinked or amphipathic block copolymers of hydrogels.

[0030] 1. Combination Therapy

[0031] The compounds of the present invention may additionally becombined with other anticancer compounds to provide an operativecombination. It is intended to include any chemically compatiblecombination of a compound of this inventive group with other compoundsof the inventive group or other compounds outside of the inventivegroup, as long as the combination does not eliminate the anticanceractivity of the compound of this inventive group. For example, one ormore benzimidazole compounds or therapeutically acceptable derivativescan be combined with other anticancer agents, chemotherapeutic agents,or potentiators. Potentiators are materials which affect the body'sresponse to the anti-cancer agent

[0032] The combination therapy can be sequential, that is the treatmentwith one agent first and then the second agent, or it can be treatmentwith both agents at the same time. The sequential therapy can be withina reasonable time after the completion of the first therapy beforebeginning the second therapy. The treatment with both agents at the sametime can be in the same daily dose or in separate doses. For exampletreatment with one agent on day 1 and the other on day 2. The exactregimen will depend on the disease being treated, the severity of theinfection and the response to the treatment. As used herein, “adjuncttherapy” means that the patient in need of the drug is treated or givenanother drug for the disease and/or a potentiator in conjunction withthe compound of the inventive gorup. Adjunct therapy can be sequentialtherapy where the patient is treated first with one compound and thenthe other within a given time period or concommitant therapy where thetwo compounds are administered substantially simultaneously or inoverlapping dosing regimens.

[0033] The benzimidazole compound generally is used in single ormultiple treatments. Alternatively, the benzimidazole compound iscombined with other therapeutic agents, chemotherapeutic agents orpotentiators to treat disorders. “Potentiators” are materials whichaffect the body's response or diseased cell's response to thebenzimidazole compound. A “potentiator” can be any material whichimproves or increases the efficacy of a pharmaceutical compositioncontaining the benzimidazole compound or acts as an immunomodulator toincrease the efficacy of the benzimidazole compound.

[0034] An exemplary potentiator is triprolidine or its cis-isomer whichare used in combination with chemotherapeutic agents and a benzimidazolecompound. Triprolidine is described in U.S. Pat. No. 5,114,951 (1992).Another potentiator is procodazole, 1H-Benzimidazole-2-propanoic acid;[β-(2-benzimidazole) propionic acid; 2-(2-carboxyethyl)benzimidazole;propazol]. Procodazole is a non-specific immunoprotective agent activeagainst viral and bacterial infections that is used with thecompositions claimed herein. It is effective with a benzimidazolecompound in the methods of the invention. Procodazole can also becombined with a benzimidazole compound and other chemotherapeutic agentsand used in the method of the invention. Other potentiators which can beused with a benzimidazole compound, and optionally anotherchemotherapeutic agent, in the methods of the invention includemacrophage colony-stimulating factor (M-CSF), 7-thia-8-oxoguanosine,6-mercaptopurine and vitamin A (retinol), monensin, an anti-senseinhibitor of the RAD51 gene, bromodeoxyuridine, dipyridamole,indomethacin, a monoclonal antibody, an anti-transferrin receptor inmmunotoxin, metoclopramide,N-solanesyl-N,N′-bis(3,4-dimethoxybenzyl)ethylenediamine, leucovorin,heparin, N-[4-[(4-fluorphenyl)sulfonly]phenyl] acetamide, heparinsulfate, cimetidine, a radiosensitizer, a chemosensitizer, a hypoxiccell cytotoxic agent, muramyl dipeptide, vitamin A, 2′-deoxycoformycin,a bis-diketopiperazine derivative, and dimethyl sulfoxide.

[0035] The chemotherapeutic agents which can be used with abenzimidazole compound and an optional potentiator are generally groupedas DNA-interactive Agents, Antimetabolites, Tubulin-Interactive Agents,Hormonal agents and others such as Asparaginase or hydroxyurea. Each ofthe groups of chemotherapeutic agents can be further divided by type ofactivity or compound. For a detailed discussion of chemotherapeuticagents and their method of administration, see Dorr, et al, CancerChemotherapy Handbook, 2d edition, pages 15-34, Appleton & Lange(Connecticut, 1994) the disclosure of which is hereby incorporated byreference.

[0036] DNA-Interactive Agents include the alkylating agents, e.g.Cisplatin, Cyclophosphamide, Altretamine; the DNA strand-breakageagents, such as Bleomycin; the intercalating topoisomerase IIinhibitors, e.g., Dactinomycin and Doxorubicin); the nonintercalatingtopoisomerase II inhibitors such as, Etoposide and Teniposde; and theDNA minor groove binder Plcamydin.

[0037] The alkylating agents form covalent chemical adducts withcellular DNA, RNA, and protein molecules and with smaller amino acids,glutathione and similar chemicals. Generally, these alkylating agentsreact with a nucleophilic atom in a cellular constituent, such as anamino, carboxyl, phosphate, sulfhydryl group in nucleic acids, proteins,amino acids, or glutathione. The mechanism and the role of thesealkylating agents in cancer therapy is not well understood. Typicalalkylating agents include:

[0038] Nitrogen mustards, such as Chlorambucil, Cyclophosphamude, Isofanude, Mechlorethamine, Melphalan, Uracil mustard;

[0039] Aziridine such as Thiotepa;

[0040] methanesulphonate esters such as Busulfan;

[0041] nitroso ureas, such as Carmustine, Lomustine, Streptozocin;

[0042] platinum complexes, such as Cisplatin, Carboplatin;

[0043] bioreductive alkylator, such as Mitomycin, and Procarbazine,Dacarbazine and Altretamine.

[0044] DNA strand breaking agents include Bleomycin.

[0045] DNA topoisomerase II inhibitors include the following:

[0046] Intercalators, such as Amsacrine, Dactinomycin, Daunorubicin,Doxorubicin, Idarubicin, and Mitoxantrone; and

[0047] nonintercalators, such as Etoposide and Teniposide.

[0048] The DNA minor groove binder is Plicamycin.

[0049] The antimetabolites interfere with the production of nucleicacids by one or the other of two major mechanisms. Some of the drugsinhibit production of the deoxyribonucleoside triphosphates that are theimmediate precursors for DNA synthesis, thus inhibiting DNA replication.Some of the compounds are sufficiently like purines or pyrimidines to beable to substitute for them in the anabolic nucleotide pathways. Theseanalogs can then be substituted into the DNA and RNA instead of theirnormal counterparts. The antimetabolites useful herein include:

[0050] folate antagonists such as Methotrexate and trimetrexate

[0051] pyrinidine antagonists, such as Fluorouracil, Fluorodeoxyuridine,CB3717, Azacitidine and Floxuridine

[0052] purine antagonists such as Mercaptopurine, 6-Thioguanine,Pentostatin;

[0053] sugar modified analogs such as Cytarabine and Fludarabine; and

[0054] ribonucleotide reductase inhibitors such as hydroxyurea.

[0055] Tubulin Interactive agents act by binding to specific sites ontubulin, a protein that polymerizes to form cellular ruicrotubules.Microtubules are critical cell structure units. When the interactiveagents bind on the protein, the cell can not form microtubules TubulinInteractive agents include colchicine, Vincristine and Vinblastine, bothalkaloids and Paclitaxel and cytoxan.

[0056] Hormonal agents are also useful in the treatment of cancers andtumors. They are used in hormonally susceptible tumors and are usuallyderived from natural sources. These include:

[0057] estrogens, conjugated estrogens and Ethinyl Estradiol andDiethylstilbesterol, Chlortrianisen and Idenestrol;

[0058] progestins such as Hydroxyprogesterone caproate,Medroxyprogesterone, and Megestrol; and

[0059] androgens such as testosterone, testosterone propionate;fluoxymesterone, methyltestosterone.

[0060] Adrenal corticosteroids are derived from natural adrenal cortisolor hydrocortisone. They are used because of their anti inflammatorybenefits as well as the ability of some to inhibit mitotic divisions andto halt DNA synthesis. These compounds include, Prednisone,Dexamethasone, Methylprednisolone, and Prednisolone.

[0061] Leutinizing hormone releasing hormone agents orgonadotropin-releasing hormone antagonists are used primarily thetreatment of prostate cancer. These include leuprolide acetate andgoserelin acetate. They prevent the biosynthesis of steroids in thetestes.

[0062] Antihornonal antigens include:

[0063] antiestrogenic agents such as Tamoxifen,

[0064] antiandrogen agents such as Flutamide; and

[0065] antiadrenal agents such as Mitotane and Aminoglutethimide.

[0066] Hydroxyurea, which appears to act primarily through inhibition ofthe enzyme ribonucleotide reductase, can also be used in combinationwith the benzimidazole compound.

[0067] Asparaginase is an enzyme which converts asparagine tononfunctional aspartic acid and thus blocks protein synthesis in thetumor. Asparaginase can also be used in combination with thebenzimidazole compound to treat cancer.

[0068] Other chemotherapeutic benzimidazoles and griseofulvin can alsobe used in combination with the benzimidazole compound and optionally apotentiator to treat or inhibit the growth of cancer or extend the lifespan of a mammal having cancer.

[0069] The amount and identity of a chemotherapeutic agent that is usedwith a benzimidazole compound in the methods of the invention will varyaccording to cellular response, patient response and physiology, typeand severity of side effects, the disease being treated, the preferreddosing regimen, patient prognosis or other such factors.

[0070] The benzimidazole compound can be used in combination with one ormore other agents or combination of agents known to possessanti-leukemia activity including, by way of example, a-interferon;interleukin-2; cytarabine and mitoxantrone; cytarabine and daunorubicinand 6-thioguanine; cyclophosphamide and 2-chloro-2′-deoxyadenosine;VP-16 and cytarabine and idorubicin or mitoxantrone; fludarabine andcytarabine and g-CSF; chlorambucil; cyclophosphamide and vincristine and(prednisolone or prednisone) and optionally doxorubicin; tyrosine kinaseinhibitor; an antibody; glutamine; clofibric acid; all-trans retinoicacid; ginseng diyne analog; KRN8602 (anthracycline drug); temozolomideand poly(ADP-ribose) polymerase inhibitors; lysofylline; cytosinearabinoside; chlythorax and elemental enteral diet enriched withmedium-chain triglycerides; amifostine; gilvusmycin; or a hot waterextract of the bark of Acer nikoense.

[0071] The benzimidazole compound can also be used in combination withother non- chemotherapeutic treatments for leukemia including bonemarrow transplant, therapeutic apheresis, radiation.

[0072] When a benzimidazole compound is used in combination with othertherapeutic agents, the ratio of the compound of the invenition to theother therapeutic agent will be varied as needed according to thedesired therapeutic effect, the observed side-effects of thecombination, or other such considerations known to those of ordinaryskill in the medical arts. Generally, the ratio of the benzimidazolecompound to other therapeutic agent will range from about 0.5% to about99.5% wt. to about 99.5% to about 0.5% wt.

[0073] When the benzimidazole compound is administered before or afterother therapeutic agents to treat viral infections, cancer, tumors, orother diseases, the respective doses and the dosing regimen of thebenzimidazole compound and the other therapeutic agent may vary. Theadjunct therapy can be sequential, that is the treatment with one agentfirst and then the second agent, or it can be concomitant treatmentwherein two or more agents are administered substantially at the sametime. The sequential therapy can be within a reasonable time after thecompletion of the first therapy before beginning the second therapy. Thetreatment with both agents at the same time can be in the same dailydose or in separate doses. For example treatment with one agent on day 1and the other on day 2. The exact regimen will depend on the diseasebeing treated, the severity of the infection and the response to thetreatment.

[0074] For example, a full dosing regimen of the benzimidazole compoundcan be administered either before or after a full dosing regimen of theother therapeutic agent, or alternating doses of the benzimidazolecompound and the other therapeutic agent may be administered. As afurther example, the benzimidazole compound can be administeredconcomitantly with the other therapeutic agent.

[0075] Propionic acid and its salts and esters can also be used incombination with the pharmaceutical compositions claimed herein.Antioxidant vitamins such as vitamins A, C and E and beta-carotene canbe added to these compositions.

[0076] 2. Unit Dosage

[0077] The compounds of the present invention may administered in a unitdosage form and may be prepared by any methods well known in the art.Such methods include combining the compounds of the present inventionwith a car mer or diluent which constitutes one or more accessoryingredients. Typically, the formulations are prepared by uniformlymixing the active ingredient with liquid carriers or finely dividedsolid carriers or both, and then if necessary shaping the product. Apharmaceutical carrier is selected on the basis of the chosen route ofadministration and standard pharmaceutical practice. Each carrier mustbe “acceptable” in the sense of being compatible with the otheringredients of the formulation and not injurious to the subject. Thiscarrier can be a solid or liquid and the type is generally chosen basedon the type of administration being used. Examples of suitable solidcarriers include lactose, sucrose, gelatin, agar and bulk powders.Examples of suitable liquid carriers include water, pharmaceuticallyacceptable fats and oils, alcohols or other organic solvents, includingesters, emulsions, syrups or elixirs, suspensions, solutions and/orsuspensions, and solution and or suspensions reconstituted fromnon-effervescent granules and effervescent preparations reconstitutedfrom effervescent granules. Such liquid carriers may contain, forexample, suitable solvents, preservatives, emulsifying agents,suspending agents, diluents, sweeteners, thickeners, and melting agents.Preferred carriers are edible oils, for example, corn or canola oils.Polyethylene glycols, e.g. PEG, are also good carriers.

[0078] Dosage forms (compositions suitable for administration) comprisefrom about 10 milligrams to about 10,000 milligrams of active ingredientper kilogram (kg) of body weight. Preferably the dosage forms willcontain from about 150 mg to about 5000 mg/kg of body weight. Mostpreferably the doses are between 1500 mg to about 5000 mg/kg of bodyweight. In these pharmaceutical compositions the active ingredient willordinarily be present in an amount of about 0.5 to about 95% by weightbased on the total weight of the dosage unit.

[0079] 3. Pharmaceutical Kits

[0080] The present invention also includes pharmaceutical kits useful,for example, for the treatment of cancer, which comprise one or morecontainers containing a pharmaceutical composition comprising atherapeutically effective amount of a benzimidazole compound ortherapeutically acceptable derivative. Such kits can further include, ifdesired, one or more of various conventional pharmaceutical kitcomponents, such as, for example, containers with one or morepharmaceutically acceptable carriers, additional containers, etc., aswill be readily apparent to those skilled in the art. Printedinstructions, either as inserts or as labels, indicating quantities ofthe components to be administered, guidelines for administration, and/orguidelines for mixing the components, can also be included in the kit.In the present disclosure it should be understood that the specifiedmaterials and conditions are important in practicing the invention butthat unspecified materials and conditions are not excluded so long asthey do not prevent the benefits of the invention from being realized.

[0081] 4. Dosage Forms

[0082] Specific examples of pharmaceutical acceptable carriers andexcipients that may be used to formulate oral dosage forms of thepresent invention are described in U.S. Pat. No. 3,903,297 to Robert,issued Sept. 2, 1975.

[0083] Techniques and compositions for making dosage forms usef uil inthe present invention are described herein below.

[0084] Oral formulations suitable for use in the practice of the presentinvention include capsules, gels, cachets, tablets, effervescent ornon-effervescent powders or tablets, powders or granules; as a solutionor suspension in aqueous or non-aqueous liquid; or as an oil-in-waterliquid emulsion or a water-in-oil emulsion. The compounds of the presentinvention may also be presented as a bolus, electuary or paste.

[0085] The formulations for oral administration may comprise anon-toxic, pharmaceutically acceptable, inert carrier such as lactose,starch, sucrose, glucose, methyl cellulose, magnesium stearate,dicalcium phosphate, calcium sulfate, mannitol, sorbitol, cyclodextrinand cyclodextrin derivatives and the like.

[0086] Capsule or tablets can be easily formulated and can be made easyto swallow or chew. Tablets may contain suitable binders, lubricants,diluents, disintegrating agents, coloring agents, flavoring agents,flow-inducing agents, and melting agents. A tablet may be made bycompression or molding, optionally with one or more additionalingredients. Compressed tables may be prepared by compressing the activeingredient in a free flowing form (e.g., powder, granules) optionallymixed with a binder (e.g., gelatin, hydroxypropylmethlcellose),lubricant, inert diluent, preservative, disintegrant (e.g., sodiumstarch glycolate, cross-linked carboxymethyl cellulose) surface-activeor dispersing agent. Suitable binders include starch, gelatin, naturalsugars such as glucose or beta-lactose, corn sweeteners, natural andsynthetic gums such as acacia, tragacanth, or sodium alginate,carboxymethylcellulose, polyethylene glycol, waxes, and the like.Lubricants used in these dosage forms include sodium oleate, sodiumstearate, magnesium stearate, sodium benzoate, sodium acetate, sodiumchloride, and the like. Disintegrators include, without limitation,starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.Molded tables may be made by molding in a suitable machine a mixture ofthe powdered active ingredient moistened with an inert liquid diluent.

[0087] The tablets may optionally be coated or scored and may beformulated so as to provide slow or controlled release of the activeingredient. Tablets may also optionally be provided with an entericcoating to provide release in parts of the gut other than the stomach.

[0088] Formulations suitable for topical administration in the mouthwherein the active ingredient is dissolved or suspended in a suitablecarrier include lozenges which may comprise the active ingredient in aflavored carrier, usually sucrose and acacia or tragacanth; gelatin,glycerin, or sucrose and acacia; and mouthwashes comprising the activeingredient in a suitable liquid carrier.

[0089] Topical applications for administration according to the methodof the present invention include ointments, cream, suspensions, lotions,powder, solutions, pastes, gels, spray, aerosol or oil. Alternately, aformulation may comprise a transdermal patch or dressing such as abandage impregnated with an active ingredient and optionally one or morecarriers or diluents. To be administered in the form of a transdermaldelivery system, the dosage administration will, of course, becontinuous rather than intermittent throughout the dosage regimen.

[0090] The topical formulations may desirably include a compound whichenhances absorption or penetration of the active ingredient through theskin or other affected areas. Examples of such dermal penetrationenhancers include dimethylsulfoxide and related analogues.

[0091] The oil phase of the emulsions of the composition used to treatsubjects in the present invention may be constituted from knowningredients in a known manner. This phase may comprise one or moreemulsifiers. For example, the oily phase comprises at least oneemulsifier with a fat or an oil or with both a fat and an oil or ahydrophilic emulsifier is included together with a lipophilic emulsifierwhich acts as a stabilizer. Together, the emulsifier(s) with or withoutstabilizer(s) make up an emulsifying was, and the wax together with theoil and/or fat make up the emulsifying ointment base which forms theoily dispersed phase of the cream formulations.

[0092] Emulsifiers and emulsion stabilizers suitable for use in theformulation include Tween 60, Span 80, cetosteryl alcohol, myristylalcohol, glyceryl monostearate and sodium lauryl sulphate, parrafin,straight or branched chain, mono-or dibasic alkyl esters, mineral oil.The choice of suitable oils or fats for the formulation is based onachieving the desired cosmetic properties, the properties required andcompatibility with the active ingredient.

[0093] The compounds may also be administered vaginally for example, aspessaries, tampons, creams, gels, pastes, foams or spray formulationscontaining in addition to the active ingredient. Such carriers are knownin the art.

[0094] Formulations for rectal administration may be presented as asuppository with a suitable base comprising, for example, cocoa butteror a salicylate.

[0095] Formulations suitable for nasal administration may beadministered in a liquid form, for example, nasal spray, nasal drops, orby aerosol administration by nebulizer, including aqueous or oilysolutions of the active ingredient. Formulations for nasaladministration, wherein the carrier is a solid, include a coarse powderhaving a particle size, for example, of less than about 100 microns,preferably less than about 50 microns, which is administered in themanner in which snuff is taken, i.e., by rapid inhalation through thenasal passage from a container of the powder held close up to the nose.

[0096] Formulations suitable for parenteral administration includeaqueous and non-aqueous isotonic with the blood of the intendedrecipient; and aqueous and non-aqueous sterile suspensions which mayinclude suspending systems which are designed to target the compound toblood components or one or more organs. The formulations may bepresented in unit-dose or multi-dose sealed containers, for example,ampoules and vials. Extemporaneous injections solutions and suspensionsmay be prepared from sterile powders, granules and tablets of the kindpreviously described.

[0097] In general, water, a suitable oil, saline, aqueous dextrose(glucose), and related sugar solutions and glycols such as propyleneglycol or polyethylene glycols are suitable carriers for parenteralsolutions. Solutions for parenteral administration preferably contain awater soluble salt of the active ingredient, suitable stabilizingagents, and if necessary, buffer substances. Antioxidizing agents suchas sodium bisulfite, sodium sulfite, or ascorbic acid, either alone orcombined, are suitable stabilizing agents. Also used are citric acid andits salts and sodium EDTA. In addition, parenteral solutions can containpreservatives, such as benzalkonium chloride, methyl- or propyl-paraben,and chlorobutanol. Suitable pharmaceutical carriers are described inRemington's Pharmaceutical Sciences, Mack Publishing Company, a standardreference text in this field.

[0098] Intravenously, the most preferred doses can range from about 1 toabout 1000 mg/kg/minute during a constant rate infusion. Thebenzimidazole compounds or therapeutically acceptable derivatives can beadministered in a single daily dose, or the total daily dosage can beadministered in divided doses of two, three, or four times daily. Thebenzimidazole compounds or therapeutically acceptable derivatives can begiven in one or more doses on a daily basis or from one to three times aweek.

[0099] The present invention additionally include administeringcompounds of the herein described formula for the use in the form ofveterinary formulations, which may be prepared, for example, by methodsthat are conventional in the art.

[0100] Useful pharmaceutical dosage forms for administration of thecompounds of this invention are illustrated as follows:

[0101] Capsules

[0102] A large number of unit capsules are prepared by filling standardtwo-piece hard gelatin capsules each with 100 milligrams of powderedactive ingredient, 150 milligrains of lactose, 50 milligrams ofcellulose, and 6 milligrams magnesium stearate.

[0103] Soft Gelatin Capsules

[0104] A mixture of active ingredient in a digestible oil such assoybean oil, cottonseed oil or olive oil is prepared and injected bymeans of a positive displacement pump into gelatin to form soft gelatincapsules containing 100 milligrams of the active ingredient. Thecapsules are washed and dried.

[0105] Tablets

[0106] A large number of tablets are prepared by conventional proceduresso that the dosage unit was 100 milligrams of active ingredient, 0.2milligrams of colloidal silicon dioxide, 5 milligrams of magnesiumstearate, 275 milligrams of microcrystalline cellulose, 11 milligrams ofstarch and 98.8 milligrams of lactose. Appropriate coatings can beapplied to increase palatability or delay absorption.

[0107] Injectable

[0108] A parenteral composition suitable for administration by injectionis prepared by stirring 1.5% by weight of active ingredient in 10% byvolume propylene glycol and water. The solution is made isotonic withsodium chloride and sterilized.

[0109] Suspension

[0110] An aqueous suspension is prepared for oral administration so thateach 5 ml contain 100 mg of finely divided active ingredient, 200 mg ofsodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g ofsorbitol solution, U.S.P., and 0.025 ml of vanillin.

[0111] Techniques and compositions for making dosage forms useful in thepresent invention are described in the following references: 7 ModemPharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors, 1979);Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); andAnsel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976).

[0112] One or more benizmidazoles can be used in a single treatment. Thebenzimidazoles can be combined with other chemotherapeutic agents orpotentiators.

D. THE BENZIMIDAZOLE COMPOUNDS

[0113] The invention compounds are benzimidazole derivatives, theirsalts, pharmaceutically acceptable derivatives or their prodrugs havingthe following structure:

[0114] wherein X is hydrogen, halogen, alkyl of less than 7 carbon atomsor alkoxy of less than 7 carbon atoms; n is a positive integer of lessthan 4; Y is hydrogen, chloro, oxychloro, nitro, methyl or ethyl; and Ris hydrogen or an alkyl group having from 1 to 8 carbons, and R₂ isNHCOOR₁ wherein R₁ is aliphatic hydrocarbon of less than 7 carbon atoms,and preferably and alkyl group of less than 7 carbon atoms.

[0115] Preferably the compounds used in the method of the presentinvention are:

[0116] wherein R is an alkyl of 1 through 8 carbon atoms and R₂ isselected from the group consisting of NHCOOR₁, wherein R₁ is methyl,ethyl or isopropyl and the non-toxic, pharmaceutically acceptable acidaddition salts with both organic and inorganic acids.

[0117] The most preferred compounds are2-methoxycarbonylamino-benzimidazole and the compounds wherein Y and Xare hydrogen. Also preferred are those with a chloro or oxychlorosubstituent in the 5 or 7 position.

[0118] These compounds are prepared according to the method described inU.S. Pat. No. 3,738,995 issued to Adams et al, Jun. 12, 1973. Thethiazolyl derivatives are prepared according to the method described inBrown et al. (J. Am. Chem. Soc. (1961), 83, 1764), and Grenda et al. (J.Org. Chem. (1965), 30, 259). Some of these compounds are alsocommercially available from BASF, Hoechst, E. I. Du Pont de Nemours, andMSD-AgVet. A synthetic organic chemist could readily ascertain how toprepare the compounds used in this invention.

E. DOSAGE

[0119] Any suitable dosage may be given in the method of the invention.The type of compound and the carrier and the amount will vary widelydepending on the species of the warm blooded animal or human, bodyweight, and tumor being treated. A dosage of as little as about 10milligrams (mg) of the active ingredient may be used in the method ofthe present invention. Generally a dosage of about 250 milligrams (mg)per kilogram (kg) of body weight and up to about 6000 mg per kg of bodyweight is suitable. Preferably from 1000 mg to about 5000 mg/kg of bodyweight is used. Most preferably the doses are between 1500 mg to about5000 mg. The doses which have shown dose responsive in vivo againstcancers are 2500 mg/kg, 3500 mg/kg, 4000 mg/kg and 5000 mg/kg. Thesedosages are in mice and generally human dosages are about one-half (½)of the mouse dose.

[0120] Typically, the dosage in man is lower than for small warm bloodedmammals such as mice. A dosage unit may comprise a single compound ormixtures thereof with other compounds or other or cancer inhibitingcompounds. The dosage unit can also comprise ingredients describedherein above. The unit may be in various forms and administered asdescribed above. The unit dosage may also be used in combination withother local treatment modalities, such at surgery and/or radiotherapy.

[0121] The benzimidazole can be given in one or more doses on a dailybasis or from one to three times a week.

[0122] The following examples are illustrative and are not meant to belimiting to the invention.

F. TEST METHODS

[0123] The Institute for Drug Development's In Vivo Laboratory hasevaluated the chemopreventive activity of Carbendazim against the Ape^(Min)mouse model and the MiaPaCa human pancreatic tumor xenograftmodel. In both studies, —Carbendazim was administered orally at 1000mg/kg, 1500 mg/kg, and 2000 mg/kg on a twice weekly to end schedule. Inorder to provide a positive control for the Ape ^(Min) mouse study,Sulindac was administered ad libitum in the drinking water at 85 mg/l.Gemcitabine at 80 mg/kg, i.p., served as the positive control in theMiaPaCa study.

[0124] Ape ^(Min)Mouse Model

[0125] Female C57BL/6J- Apc ^(Min) mice were obtained from The JacksonLaboratory at 4-5 weeks of age. The following day (Day 1), drugtreatment begins. The Min (Multiple intestinal neoplasia) mouse is astrain with a mutated murine Apc (adenoinatous polyposis coli) gene,which leads to the development of multiple intestinal polyps. Thisdevelopment is time and diet dependent, with 100% of the mice whichingest a high fat diet forming adenomas beginning around 45 days of age.These mice develop in excess of 30 adenomas throughout the intestinaltract during their 120 day life span and are therefore an ideal modelfor the evaluation of potential chemopreventive agents.

[0126] The mean survival times of all groups were calculated, andresults are expressed as mean survival of treated mice/mean survival ofcontrol mice (T/C)×100%. A T/C value of 150 means that the mice in thetreated group lived 50% longer than those of the control group; this issometimes referred to as the increase in life span, or ILS value.

[0127] Statistics were performed on the data using primarily the logrank p-value test. The results are shown below in Table 1. TABLE 1Carbendazim vs. Min Mouse Model Avg. Age - 118 Days # of non- Tumor #specific Group n Dose Route Schedule ±S.D. p-value Death Control (10)Peanut Oil p.o. 2× weekly to 31.70 ± — 0 end 18.49 Carbendazim (10) 1000mg/kg p.o. 2× weekly to 24.71 ± 7.8 p = 0.364 3 end Carbendazim (10)1500 mg/kg p.o. 2× weekly to 13.25 ± p = 0.015 2 end 4.83 Carbendazim(9) 2000 mg/kg p.o. 2× weekly to 19.17 ± p = 0.139 3 end 7.36 Sulindac(9) 0.85 mg/kg p.o. ad 16.33 ± p = 0.027 0 libitum/H20 4.69

[0128] The results with Carbendazim and the Min mouse model are shown inTable 1. The average number of intestinal tumors were 31.7 in peanut oilcontrols compared to 24.7, 13.2, and 19.1 in animals administeredCarbendazim at 1000, 1500, and 2000 mg/kg, respectively. Animals treatedwith Sulindac had a mean intestinal tumor number of 16.3. Treatment withCarbendazim (1500 mg/kg) and Sulindac resulted in a significant p<0.05)decrease in the number of intestinal tumors compared to animals givenpeanut oil. There was no significant difference in the number ofintestinal tumors between groups administered Carbendazim at 1500 mg/kgand those treated with Sulindac. These animals had relatively few tumorsat 111 days which is their normal life span.

[0129] Colon, Breast and Lung Tumor Cells Test

[0130] The following cell culture tests were performed to test thetoxicity of the benzimidazole compounds on colon, breast and lung humantumor cells. The viability of the cells were tested by looking at MTT(3-[4,5-dimethylthiazol-2-yl] -2,5-diphenyltetrazolium bromide)reduction. MTT assay is a well known measure of cell viability.

[0131] The colon tumor cells (HT29 from American Type Culture Collection(ATCC) ) and the breast cells (MXI from cell lines from ATCC) werecultured in Eagle's Miminal Essential Medium with 10% fetal bovineserum. The lung tumor cells (A549 from ATCC cell lines) were cultured inHam's F12 medium with 10% fetal bovine serum.

[0132] The tumor cells were passaged and seeded into culture flasks atthe desired cell densities. The culture medium was decanted and the cellsheets were washed twice with phosphate buffered saline (PBS). The cellswere trypsinized and triturated prior to seeding the flasks. Unlessotherwise indicated the cultures were incubated at 37±1° C. in ahumidified atmosphere of 5±1 % carbon dioxide in air. The cultures wereincubated until they were 50-80% confluent.

[0133] The cells were subcultured when the flasks were subconfluent. Themedium was aspirated from the flasks and the cell sheets rinsed twicewith PBS. Next, the Trypsin Solution was added to each flask to coverthe cell sheet. The Trypsin Solution was removed after 30-60 seconds andthe flasks were incubated at room temperature for two to six minutes.When 90% of the cells became dislodged, growth medium was added. Thecells were removed by trituration and transferred to a sterilecentrifuge tube. The concentration of cells in the suspension wasdetermined, and an appropriate dilution was made to obtain a density of5000 cells/ml. The cells were subcultured into the designated wells ofthe 96-well bioassay plates (200 microliter cell suspension per well).PBS was added to all the remaining wells to maintain humidity. Theplates were then incubated overnight before test article treatment.

[0134] Each dose of test article was tested by treating quadruplicatewells of cultures with 100 microliter of each dilution. Those wellsdesignated as solvent controls received an additional 100 microliter ofmethanol control; negative controls wells received an additional 100microliters of treatment medium. PBS was added to the remaining wellsnot treated with test article or medium. The plates were then incubatedfor approximately 5 days.

[0135] At the end of the 5 day incubation, each dose group was examinedmicroscopically to assess toxicity. A 0.5 mg/ml dilution of MTT was madein treatment medium, and the dilution was filtered through a 0.45micrometer filter to remove undissolved crystals. The medium wasdecanted from the wells of the bioassay plates. Immediately thereafter,2000 microliter of the filtered MTT solution was added to all test wellsexcept for the two untreated blank test wells. The two blank wellsreceived 200 microliters of treatment medium. The plates were returnedto the incubator for about 3 hours. After incubation, the MTT containingmedium was decanted. Excess medium was added to each well and the plateswere shaken at room temperature for about 2 hours.

[0136] The absorbance at 550 nm (OD ₅₅₀) of each well was measured witha Molecular Devices (Menlo Park, Calif.) VMax plate reader.

[0137] The mean OD₅₀₀of the solvent control wells and that of each testarticle dilution, and that of each of the blank wells and the positivecontrol were calculated. The mean OD₅₅₀ of the blank wells wassubtracted from the mean of the solvent control wells, and test articlewells, respectively to give the corresponding mean OD₅₅₀.${\% \quad {of}\quad {Control}} = {\frac{\begin{matrix}{{corrected}\quad {mean}\quad {OD}_{550}\quad {of}} \\{{Test}\quad {Article}\quad {Dilution}}\end{matrix}}{\begin{matrix}{{corrected}\quad {mean}\quad {OD}_{550}\quad {of}} \\{{Solvent}\quad {Control}}\end{matrix}} \times 100}$

[0138] Dose response curves were prepared as semi-log plots with % ofcontrol on the ordinate (linear) and the test article concentration onthe abscissa (logarithmic). The EC₅₀ was interpolated from the plots foreach test article.

[0139] For the test articles administered in methanol, separateresponses were prepared to correct for the methanol data.

[0140] Adriamycin was used as a positive control. In all cases, it wasmore toxic than any of the test materials by one or two logs.Adriarnycin is one of the more potent agents in current use and one withsignificant side effects. The peak plasma concentration of other, quiteeffective chemotherapeutic agents may be 10 to 50 times higher than thatof Adriamycin.

[0141] The EC₅₀ is the concentration at which one half of the cells arekilled. TABLE 2 EC-50 Result (ppm) Test Material HT29 HT29 MX1 MX1 A549A549 Adriamycin 0.03 0.006 0.02 0.001 0.03 0.009 benomyl 0.742 0.7471.42 2.42 0.980 1.02 carbendaziin 0.621 0.662 0.829 0.856 0.856 0.836

[0142] In normal healthy cells, the following results were obtained. Asis evident, the benomyl and carbendazim were much less toxic to normalhealthy cells than adriamycin. TABLE 3 Test Material EC-50 Kero- Fibro-Broncheal Cells tinoyle Cells blasts Benomyl 0.728 0.682 3.26 2.4 3.242.81 Carbendazin 0.320 0.506 0.752 0.822 1.52 1.42 Adriamycin 0.0150.0020 0.0035 0.0093 0.065 0.10

What is claimed is:
 1. A method of preventing cancer in a subject atrisk for developing cancer comprising administering to said subject apharmaceutical composition comprising a therapeutically effective amountof a pharmaceutically acceptable prodrug of a benzi ridazole having theformula:

wherein X is hydrogen, halogen, alkyl of less than 7 carbon atoms, oralkoxy of less than 7 carbon atoms; n is a positive integer of less than4; Y is hydrogen, chloro, nitro, oxychloro, methyl or ethyl; R ishydrogen or an alkyl group having from 1 to 8 carbon atoms; and R₂ isNHCOOR₁ wherein R₁ is aliphatic hydrocarbon of less than 7 carbon atomswherein cancer is prevented in the subject thereby.
 2. A methodaccording to claim 1 wherein the composition comprises apharmaceutically acceptable prodrug of2-methoxycarbonylarninobenzimidazole.
 3. A method according to claim 1wherein the therapeutically effective amount is from 500 mg/kg bodyweight to 6000 mg/kg body weight of the benzir nidazole.
 4. A methodaccording to claim 1 wherein the cancer is colon cancer.
 5. A methodaccording to claim 1 wherein the cancer is pancreatic cancer.
 6. Amethod according to claim 1 wherein the cancer is breast cancer.
 7. Amethod according to claim 1 wherein the cancer is lung cancer.
 8. Amethod according to claim 1 wherein the cancer is leukemia.
 9. A methodaccording to claim 1 wherein the cancer is sarcoma.
 10. A methodaccording to claim 1 wherein the prodrug is micronized.
 11. A method ofinhibiting metastasis of a cancer susceptible to treatment in a subjectat risk for metastasis of cancer comprising adminriistering to saidsubject a pharmaceutical composition comprising a therapeuticallyeffective amount of a pharmaceutically acceptable prodrug of abenzimidazole having the formula:

wherein X is hydrogen, halogen, alkyl of less than 7 carbon atoms, oralkoxy of less than 7 carbon atoms; n is a positive integer of less than4; Y is hydrogen, chloro, nitro, oxychloro, methyl or ethyl; R ishydrogen or an alkyl group having from 1 to 8 carbon atoms; and R₂ isNHCOOR₁ wherein R₁ is aliphatic hydrocarbon of less than 7 carbon atomswherein metastasis of the cancer is inhibited in the subject thereby.12. A method according to claim 11 wherein the composition comprises apharmaceutically acceptable prodrug of2-methoxycarbonylaimnnobenziniidazole.
 13. A method according to claim11 wherein the therapeutically effective amount is from 500 mg/kg bodyweight to 6000 mg/kg body weight of the benzimidazole.
 14. A methodaccording to claim 11 wherein the cancer is colon cancer.
 15. A methodaccording to claim 11 wherein the cancer is pancreatic cancer.
 16. Amethod according to claim 11 wherein the cancer is breast cancer.
 17. Amethod according to claim 11 wherein the cancer is lung cancer.
 18. Amethod according to claim 11 wherein the cancer is leukemia.
 19. Amethod according to claim 11 wherein the cancer is sarcoma.
 20. A methodaccording to claim 11 wherein the prodrug is micronized.